Histamine is a chemical messenger involved in various complex biological actions. When released histamine interacts with specific macromolecular receptors on the cell surface or within a target cell to elicit changes in many different bodily functions. Various cell types including smooth muscle, blood cells, cells of the immune system, endocrine and exocrine cells as well as neurons respond to histamine by stimulating the formation of intracellular signals, including formation of phosphatidylinositol or adenylate cyclase. Evidence that histamine plays a role as a neurotransmitter was established by the mid to late 1970's (Schwartz, 1975) Life Sci. 17: 503-518. Immunohistochemical studies identified histaminergic cell bodies in the tuberomammillary nucleus of the posterior hypothalamus with widespread projections in the dicencephalon and telencephalon (Inagaki et al., 1988) J. Comp. Neurol. 273: 283-300.
Identification of two histamine receptors (H.sub.1 and H.sub.2) was reported to mediate the biochemical actions of histamine on neurons. Recently, studies have demonstrated the existence of a third subtype of histamine receptor, the histamine H.sub.3 receptor (Schwartz et al., 1986) TIPS 8: 24-28. Various studies have now demonstrated that histamine H.sub.3 receptors are found on the histaminergic nerve terminals in the brains of several species, including man (Arrang et al., 1983) Nature 302: 832-837. The H.sub.3 receptor found on the histaminergic nerve terminal was defined as an autoreceptor and could intimately control the amount of histamine released from the neurons. Histamine, the natural compound, was capable of stimulating this autoreceptor but when tested against known H.sub.1 and H.sub.2 receptor agonists and antagonists, a distinct pharmacological profile emerged. Further, H.sub.3 receptors have been identified on cholinergic, serotoninergic and monoamine nerve terminals in the peripheral nervous system (PNS) and central nervous system including the cerebral cortex and cerebral vessels. These observations suggest that H.sub.3 receptors are uniquely located to modulate histamine as well as other neurotransmitter release, and H.sub.3 agonists could be important mediators of neuronal activity.
As stated, CNS histaminergic cell bodies are found in the magnocellular nuclei of the hypothalamic mammillary region and these neurons project diffusely to large areas of the forebrain. The presence of histaminergic cell bodies in the tuberomamillary nucleus of the posterior hypothalamus, a brain area involved in the maintenance of wakefulness, and their projections to the cerebral cortex suggest a role in modulating the arousal state or sleep-wake cycle. The histaminergic projection to many limbic structures such as the hippocampal formation and the amygdaloid complex suggest roles in functions such as autonomic regulation, control of emotions and motivated behaviors, and memory processes.
The concept that histamine is important for the state of arousal, as suggested by the location of histaminergic pathways, is supported by other types of evidence. Lesions of the posterior hypothalamus is well known to produce sleep. Neurochemical and electrophysiological studies have also indicated that the activity of histaminergic neurons is maximal during periods of wakefulness and is suppressed by barbiturates and other hypnotics. Intraventricular histamine induces the appearances of an arousal EEG pattern in rabbits and increased spontaneous locomotor activity, grooming and exploratory behavior in both saline ad pentobarbital-treated rats.
In contrast, a highly selective inhibitor of histidine decarboxylase, the sole enzyme responsible for histamine synthesis, has been shown to impair waking in rats. These data support the hypothesis that histamine may function in modulating behavioral arousal. The role of the H.sub.3 receptor in sleep-waking parameters has been recently demonstrated (Lin et al., 1990) Brain Res. 529: 325-330. Oral administration of RAMHA, a H.sub.3 agonist, caused a significant increase in deep slow wave sleep in the cat. Conversely, thioperamide, a H.sub.3 antagonist, enhanced wakefulness in a dose-dependent fashion. Thioperamide has also been shown to increase wakefulness and decrease slow wave and REM sleep in rats. These findings are consistent with in vivo studies demonstrating that RAMHA, can decrease and conversely, thioperamide can increase the synthesis and release of histamine. Together, these data suggest that selective H.sub.3 agonists may be useful in the treatment of hyperarousal states such as sleep disorders characterized by hyposomnolence or insomnia.
Serotonin, norepinephrine, dopamine, and acetylcholine release have all been demonstrated to be to regulated by the histamine H.sub.3 receptor. These neurotransmitters are known to play a role in many CNS psychiatric disorders involving emotional or higher cognitive function. Consequently, an H.sub.3 receptor agonist would therefore be expected to decrease the release of these neurotransmitters in brain. H.sub.3 receptor agonists might reduce states of hyperarousal via decreasing levels of neurotransmitter release and provide therapeutic approaches to the treatment of various CNS diseases characterized by emotional imbalance, anxiety or hyperarousal.
H.sub.3 receptor agonists may be useful in treating several other CNS disorders. It has been suggested that histamine may be involved in the control of sleep/wake states, states of arousal and alertness, cerebral circulation and migraine, energy metabolism, and hypothalmic hormone secretion.
In spite of their low density, H.sub.3 receptor binding sites can be detected outside the brain. The presence of H.sub.3 receptors on the sympathic and parasympathetic nerve terminals suggest uses of H.sub.3 agonists in regulating the peripheral autonomic nervous system. Several studies have revealed the presence of H.sub.3 heteroreceptors in the gastrointestinal tract, as well as upon neurons of the respiratory tract. Accordingly, an H.sub.3 receptor agonist may be useful in the treatment of diseases and conditions such as allergy, asthma, rhinitis, airway congestion, inflammation, hyper and hypo motility and acid secretion of the gastrointestinal tract. Peripheral or central stimulation of H.sub.3 receptors may also contribute to changes in blood pressure, heart rate and cardiovascular output and could be used in the treatment of cardiovascular diseases. Recent evidence has indicated the possible use of H.sub.3 agonists in the treatment of cardiac ischemia and glaucoma.
U.S. Pat. No. 4,767,778 (Aug. 30, 1988) discloses compounds of the general formula: ##STR2## in which R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are each hydrogen, or methyl, and at least one but not more than two of R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are methyl, or two of R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are together methylene.
WO 93/12107 (Jun. 24, 1993) discloses compounds of general formula: ##STR3## where m is an integer selected from the group consisting of 1 and 2;
n and p are integers and are each independently selected from the group consisting of: 0, 1, 2, 3, and 4 such that the sum of n and p is 4 and T is a 6-membered ring; PA1 R.sup.3 and R.sup.4 are each independently bound to the same or different carbon atom of ring T such that there is only one R.sup.3 group and one R.sup.4 group in ring T, and each R.sup.1, R.sup.2, R.sup.3, and R.sup.4 is independently selected from the group consisting of: PA1 (1) H; PA1 (2) C.sub.1 to C.sub.6 alkyl; and PA1 (3) --(CH.sub.2).sub.q --R.sup.6 wherein q is an integer of: 1 to 7, and R.sup.6 is selected from the group consisting of: phenyl, substituted phenyl, --OR.sup.7, --C(O)OR.sup.7, --C(O)R.sup.7, --OC(O)R.sup.7, --C(O)NR.sup.7 R.sup.8, CN and --SR.sup.7 wherein the substituents on said substituted phenyl are each independently selected from the group consisting of: --OH, --O--(C.sub.1 to C.sub.6) alkyl, halogen, C.sub.1 to C.sub.6 alkyl, --CF.sub.3, --CN, and --NO.sub.2, and wherein said substituted phenyl contains from 1 to 3 substituents; R.sup.5 is selected from the group consisting of: PA1 n and p are integers and are each independently selected from the group consisting of: 0, 1, 2, 3, and 4 such that the sum of n and p is 2 or 3 such that the sum of n and p is 2, T is a 4-membered ring and when the sum of n and p is 3, T is a 5-membered ring; PA1 each R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, and R.sup.8 is independently selected from the group consisting of: PA1 R.sup.1 is selected from the group consisting of: PA1 (1) H; PA1 (2) C.sub.1 to C.sub.6 alkyl; PA1 (3) allyl; and PA1 (4) propargyl; PA1 R.sup.3 and R.sup.4 are independently selected from the group consisting of: PA1 (1) H; PA1 (2) C.sub.1 to C.sub.6 alkyl; PA1 (3) allyl; and PA1 (4) propargyl; PA1 (5) --(CH.sub.2).sub.q --R.sup.5 wherein q is an integer of: 1 to 7, and R.sup.5 is selected from the group consisting of: phenyl, substituted phenyl, --OR.sup.6, --C(O)OR.sup.6, --C(O)R.sup.6, --OC(O)R.sup.6, --C(O)NR.sup.6 R.sup.7, CN and --SR.sup.6 wherein R.sup.6 and R.sup.7 are as defined below, and wherein the substituents on said substituted phenyl are each independently selected from the group consisting of: --OH, --O--(C.sub.1 to C.sub.6) alkyl, halogen, C.sub.1 to C.sub.6 alkyl, --CF.sub.3, --CN, and --NO.sub.2, and wherein said substituted phenyl contains from 1 to 3 substituents; R.sup.6 and R.sup.7 are each independently selected from the group consisting of: H and C.sub.1 to C.sub.6 alkyl; and R.sup.3 and R.sup.4 are each independently bound to the same or different carbon atom of ring T. PA1 R.sub.1 is lower alkyl or lower alkoxy; PA1 R.sub.2,R.sub.3,R.sub.4,R.sub.5,R.sub.7 and R.sub.8 are each independently hydrogen or lower alkyl; PA1 R.sub.6 is lower alkyl or lower alkoxy and R.sub.5 and R.sub.6 can be joined to form a 4, 5, or 6 membered ring. PA1 R.sub.1 is hydrogen, lower alkyl or lower alkoxy; PA1 R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.7 and R.sub.8 are each independently hydrogen or lower alkyl; PA1 R.sub.6 is hydrogen, lower alkyl or lower alkoxy and R.sub.5 and R.sub.6 can be joined to form a 4, 5 or 6 membered ring.
(1) H; PA2 (2) C.sub.1 to C.sub.20 alkyl; PA2 (3) C.sub.3 to C.sub.6 cycloalkyl; PA2 (4) --C(O)OR.sup.7' ; wherein R.sup.7' is the same as R.sup.7 defined below except that R.sup.7' is not H; PA2 (5) --C(O)R.sup.7 ; PA2 (6) --C(O)NR.sup.7 R.sup.8 ; PA2 (7) allyl; PA2 (8) propargyl; and PA2 (9) --(CH.sub.2).sub.q --R.sup.6, wherein q and R.sup.6 are defined as above, and when q is equal to 1, then R.sup.6 is not OH or SH; R.sup.7 and R.sup.8 are each independently selected from the group consisting of: H, C.sub.1 to C.sub.6 alkyl, and C.sub.3 to C.sub.6 cycloalkyl; the dotted line (-----) represents a double bond that is optionally present when m is 1, and n is not 0, and p is not 0 (i.e., the nitrogen in the ring is not bound directly to the carbon atom bearing the double bond), and when said double bond is present then R.sup.2 is absent; and when m is 2, each R.sup.1 is the same or different substituent for each m, and each R.sup.2 is the same or different for each m, and at least two of the sustituents R.sup.1 and/or R.sup.2 are H. PA2 (1) H; PA2 (2) C.sub.1 to C.sub.6 alkyl; PA2 (3) C.sub.3 to C.sub.6 cycloalkyl; and PA2 (3) --(CH.sub.2).sub.q --R.sup.9 wherein q is an integer of: 1 to 7, and R.sup.9 is selected from the group consisting of: phenyl, substituted phenyl, --OR.sup.10, --C(O)OR.sup.10, --C(O)R.sup.10, --OC(O)R.sup.10, --C(O)NR.sup.10 R.sup.11, CN and --SR.sup.10 wherein R.sup.10 and R.sup.11 are defined below, and wherein the substituents on said substituted phenyl are each independently selected from the group consisting of: --OH, --O--(C.sub.1 to C.sub.6) alkyl, halogen, C.sub.1 to C.sub.6 alkyl, --CF.sub.3, --CN, and --NO.sub.2, and wherein said substituted phenyl contains from 1 to 3 substituents; examples of --(CH.sub.2).sub.q --R.sup.9 include benzyl, substituted benzyl and the like, wherein the substituents on the substituted benzyl are as defined above for said substituted phenyl; R.sup.5 is selected from the group consisting of:
WO 93/12108 (Jun. 24, 1993) discloses compounds of general formula: ##STR4## where m is an integer selected from the group consisting of 0, 1, and 2;
(1) H; PA3 (2) C.sub.1 to C.sub.20 alkyl; PA3 (3 ) C.sub.3 to C.sub.6 cycloalkyl; PA3 (4) --C(O)OR.sup.10' ; wherein R.sup.10' is the same as R.sup.10 defined below except that R.sup.10' is not H; PA3 (5) --C(O)R.sup.10 ; PA3 (6) --C(O)NR.sup.10 R.sup.11 ; PA3 (7) allyl; PA3 (8) propargyl; and PA3 (9) --(CH.sub.2).sub.q --R.sup.9, wherein q and R.sup.9 are defined as above, and when q is equal to 1, then R.sup.9 is not --OH or --SH; R.sup.10 and R.sup.11 are each independently selected from the group consisting of: H, C.sub.1 to C.sub.6 alkyl, and C.sub.3 to C.sub.6 cycloalkyl; and for the substituent --C(O)NR.sup.10 R.sup.11, R.sup.10 and R.sup.11, together with them nitrogen to which they are bound, can form a ring having 5,6, or 7 atoms; the dotted line (---) represents a double bond that is optionally present when m is 1, and T is a 5-membered ring, and n is not 0, and p is not 0 (i.e., the nitrogen in the ring is not bound directly to the carbon atom bearing the double bond), and when said double bond is present then R.sup.2 and R.sup.8 are absent; when m is 2, each R.sup.1 is the same or different substituent for each m, and each R.sup.2 is the same or different for each m; when n is 2 or 3, each R.sup.3 is the same or different substituent for each n, and each R.sup.4 is the same or different substituent for each n; and PA3 when p is 2 or 3, each R.sup.6 is the same or different substituent for each p, and each R.sup.7 is the same or different substituent for each p.
WO 93/12093 (Jun. 24, 1993) discloses compounds of general formula: ##STR5## where n is 1 or 2, such that when n is 1 then ring T is a six membered ring, and when n is 2 then ring T is a seven membered ring;
4(5)-(4-Aminocyclohexyl)-1H-imidazole is disclosed in Arch. Pharmaz. p.934-942, vol. 306, 1973 by W. Schunack and was shown to be inactive as an antihistamine agent.
2-(4-imidazoyl)-cyclopropylamine when tested as a racemic mixture is disclosed as having moderate H.sub.3 histamine receptor agonist activity in U.S. Pat. No. 4,767,778.